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THALAMOSS Informe resumido

Project ID: 306201
Financiado con arreglo a: FP7-HEALTH
País: Italy

Periodic Report Summary 2 - THALAMOSS (THALAssaemia MOdular Stratification System for personalized therapy of beta-thalassemia)

Project Context and Objectives:
Summary description of the THALAMOSS project and general objectives. Development of a universal set of techniques for the stratification of β-thalassemia patients into treatment subgroups for (a) onset and frequency of blood transfusions, (b) choice of iron chelation, (c) application of chemical inducers of endogenous fetal hemoglobin (HbF), (d) prospective efficacy of gene-therapy (GT) intervention with globin-expressing vectors. A combination of these modular techniques into an integrated approach would allow more accurate genetic counseling of carrier couples at risk and comprehensive guidance of therapeutic interventions for β-thalassemia patients. These objectives will be reached by the scientific and management activity included in several Workpackages with specific objectives. The objectives of WP1 are recruitment of β-thalassemia patients, their characterization with respect to mutations of the β-globin genes, SNPs, HbF starting levels, phenotype, clinical pattern; objective of this WP is also the optimization of cell cultures from PB of β-thalassemia patients. In addition cellular biobanks will be produced. The goal of WP2 is to stratify patients with β-thalassemic mutations at the genomic, transcriptomic and proteomic levels. Newly identified potential disease modifiers will be tested functionally. These OMICS analyses will provide biomarkers for therapeutic management (categorization, prognosis, diagnosis and therapy), and identify novel potential therapeutic targets. Information from this WP will allow design of DNA- and protein-based diagnostic platforms for classification of β-thalassemia patients. All data will be fed into WP4 (Data management and analysis), allowing correlation of genotype analyses, transcriptomic data and proteomic information with clinical data (WP1) and therapeutic-driven studies (WP3), also towards the development of THALAMOSS diagnostic kits and marker-based prediction of treatment outcomes. The WP3 objective is to treat ErPC cultures from patients with novel therapeutic approaches and determine their responsiveness as additional parameters to the analyses performed in WP2 and the subsequent patient stratification in WP4. Using standardized ErPC cultures this WP will: (a) assess HbF induction by different chemical agents; (b) evaluate the therapeutic action of co-treatment with read-through molecules for samples with primary stop-codon mutations; (c) quantitate the responsiveness to GT. The major objective of WP4 is to build the infrastructure to enable multi-institutional gathering and processing of patient data and to define the correlation of genomics, proteomics and functional-genomics findings with medical records and cell culture analyses. The objectives of WP5 and WP6 are dissemination, provision of high-level training and promotion a dialogue with the wider scientific and lay communities across Europe on thalassemia and related societal and ethical issues. The second goal is exploitation. Finally ethical issues and gender actions are tackled.

Project Results:
Main strategy, description of the work performed and main results achieved so far. Acquisition of peripheral blood (PB) samples from patients (n≥800) for genetic (SNP) analysis. Determination by direct sequencing of all the genetic defects. Establishment of a standard cell culture protocol for erythroid precursor cells (ErPCs) and creation of a centralized THALAMOSS cellular Bio-Bank constituted of ErPCs from more than 120 patients carrying different genotypes. The genomic DNA of all these bio-banked cells has been fully characterized for the most important polymorphism associated with high fetal hemoglobin production, such as XmnI and polymorphisms of the BCL11A and MYB loci. Identification of novel polymorphism associated with HbF and characterization of novel transcription inhibitors of the human γ-globin genes. Transcriptomic and proteomic analysis was performed with the aim of identifying regulatory genes playing a role in the production of HbF. It was demonstrated that ErPCs from β-thalassemia patients expressing different levels of HbF exhibit transcriptomic and proteomic profiles different to those exhibited by ErPCs from patients producing low HbF levels. Studies on ErPCs from β-thalassemia patients and treated with different HbF inducers. This part of the project was aimed to (a) characterize and compare known HbF inducers and (b) identify novel HbF inducers. Drug repositioning/repurposing was also considered. Among known inducers characterized with respect to their mechanism of action are mithramycin, rapamycin, resveratrol and decitabine. Some of these HbF inducers were found to be more active that hydroxyurea (the reference HbF inducer, considering its current use in clinical trials). Combined treatment were also successfully undertaken. Novel HbF inducers were identified. Novel screening systems have been developed for HbF inducers and correctors of stop-codon mutations. Correction of the molecular defect with standard and customized (mutation-specific or HbF-inducing) lentiviral vectors was performed. Suitable infrastructures were developed to enable multi-institutional gathering and processing of patient data and to define the correlation of genomics, proteomics and functional-genomics findings with medical records and cell culture analyses. Bioethical requirements were fully achieved. Gender actions were undertaken. In the forthcoming THALAMOSS activities medical records and cell-culture analyses will be correlated with genetic, proteomics and functional genomics findings. Assessments will include the combination of known disease modifiers, such as BCL11A, KLF1, SOX6 and HPFH mutations, and determination of novel SNP, mRNA and protein markers, towards (a) more reliable prediction of expected phenotypes of novel subclasses for genetic counseling, (b) optimized treatment with conventional therapies and (c) an establishment of personalized-medicine therapies for the novel approaches of HbF induction and lentiviral GT.

Potential Impact:
Expected final results and their potential impact and use. The expected final results of THALAMOSS will be the development of a universal set of techniques for the stratification of β-thalassemia patients into treatment subgroups for diagnostic and prognostic purposes as well as for optimizing the therapeutic management of the β-thalassemia patients. The concept developed by THALAMOSS and the expected results and deliverables are relevant to the development of technologies with a view to patient group stratification for personalized medicine applications. In particular, THALAMOSS will conduct research activities that will bring important information in the field of personalized medicine, i.e. tailored medical interventions which are more effective and have fewer adverse effects in specifically defined patient groups. This will bring important changes in patients’ attitudes and the need for molecular diagnoses. In addition, the THALAMOSS results will be of relevant impact also for other sections of the applied research, such as targeting nucleic acid as an innovative therapeutic approach, omics for rare diseases, databases, biobanks and 'clinical bio-informatics', new methodologies for health technology assessment. The scientific impact of the THALAMOSS Project is expected to be excellent, in view of the fact that, for the first time, genetists, clinicians, molecular biologists, experts in gene therapy and experts in the field of induction of fetal hemoglobin are included in a common Project aimed at solving very important points in basic as well as applied research on thalassaemia. Together with sickle cell anaemia (SCA), the thalassemia syndromes are the most important problems in developing countries, in which the lack of genetic counseling and prenatal diagnosis have contributed to the maintenance of a very high frequency of these genetic diseases in the population. This contributes significantly to driving changes in the distribution of carriers and affected people in relation to the migration of populations from endemic areas to countries where their prevalence in indigenous populations had been traditionally low. These deep changes have encouraged most of the health systems of these countries in facilitating access to the prevention and treatment services available for these hemoglobin disorders. On the other hand, considering limitations and side effects of the currently available therapeutic approaches and management of the thalassemia patients, novel alternative options for therapy are urgently needed. The THALAMOSS therapeutic strategies are expected to have a clear impact in developing countries, where affected patients and healthy carriers are numerous, mainly due to the absence of genetic counseling and prenatal diagnosis. It should be underlined that several developing countries are unable to efficiently sustain the high-cost clinical management of β-thalassaemia patients requiring a regular transfusion regimen, chelating therapy and advanced hospital facilities. It is well known that, in addition to “direct costs”, blood transfusions require accurate monitoring of the blood safety using expensive technologies, some of which are based on multiple PCRs covering all the possible haematological infectious diseases. Finally, THALAMOSS is expected to bring a novel advanced integrative approach to optimize cellular therapy combined with gene therapy and gene correction.

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Francesco Bernardi, (Director)
Tel.: +39 0532 293377
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